RESUMEN
Autoantibodies have been detected in leprosy patients, indicating that infection with M. leprae may lead to autoimmune disorders. However, whether autoimmune response last until patients are cured is unknown. Knowing the autoimmune response in cured leprosy patients is essential to identify whether symptoms are caused by leprosy itself or by other immune-related diseases. This knowledge is essential for the ongoing health management in cured leprosy patients where autoimmune disorders still exist. In our study, we selected six autoantibodies, including anticardiolipin antibody of IgG (ACA), anti-nuclear antibody (ANA), extractable nuclear antigen antibody (ENA), anti-streptolysin O (ASO), anti-double stranded DNA antibody (dsDNA), and rheumatoid factor (RF), that had been reported in leprosy patients as typical autoantibodies. We tested the six typical autoantibodies combined with LACC1, which encodes a protein associated with autoimmune disease such as Crohn's disease and is also the susceptible gene conferring leprosy risk, in cured leprosy patients through ELISA to assess the cured patient's immune status. We observed high positive rates of autoantibodies in cured leprosy patients, and the average plasma levels of five (ACA, ANA, ENA, ASO, and RF) out of the six autoantibodies were significantly higher in cured leprosy patients than in controls. The positive detection of autoantibodies is independent of the recovery period. Moreover, the level of these autoantibodies showed a strong positive correlation with the level of LACC1 in both controls and cured patients. This study showed that there is long-term autoimmunological activation in leprosy patients, even after decades of recovery. Autoimmune responses may influence the development and prognosis of leprosy. Special care should be given to posttreatment or cured leprosy patients regarding long-term autoimmunological activation.
Asunto(s)
Enfermedades Autoinmunes , Lepra , Humanos , Autoanticuerpos , Anticuerpos Antinucleares , Factor Reumatoide , Mycobacterium lepraeRESUMEN
Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 × 10-9, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 × 10-18, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis.
Asunto(s)
Pueblo Asiatico/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Lepra/genética , Mutación Missense/genética , Proteínas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Niño , Estudios de Cohortes , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factores de Riesgo , Transactivadores/genética , Regulación hacia Arriba/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: The pathogen Mycobacterium leprae of leprosy is heavily dependent on the host energy metabolites and nutritional products for survival. Previously we and others have identified associations of several mitochondrion-related genes and mitochondrial DNA (mtDNA) copy number alterations with leprosy and/or its subtype. We hypothesized that genetic variants of mtDNA replication-related genes would affect leprosy. OBJECTIVE: We aimed to identify genetic associations between the mtDNA replication-related genes TFAM, POLG and leprosy. METHODS: Genetic association study was performed in 2898 individuals from two independent sample sets in Yunnan Province, China. We first screened 7 tag SNPs of TFAM and POLG in 527 leprosy cases and 583 controls (Sample I). Expression quantitative trait loci (eQTL) analysis and differential mRNA expression were analyzed to discern potential effect of risk variants. The entire exon region of TFAM and POLG were further analyzed in 798 leprosy cases and 990 controls (Sample II; 4327 East Asians from the ExAC dataset was included as a reference control) by using targeted gene sequencing for fine mapping potentially causal variants. RESULTS: Two tag SNPs of TFAM (rs1049432, P=0.007) and POLG (rs3176238, P=0.006) were associated with multibacillary leprosy (MB) in Sample I and the significance survived correction for multiple comparisons. SNPs rs1937 of TFAM (which was linked with rs1049432) and rs61756401 of POLG were associated with leprosy, whereas no potentially causative coding variants were identified in Sample II. The eQTL analysis showed that rs1049432 was a significant cis eQTL for TFAM in nerve tissue (P=1.20×10-12), and rs3176238 was a significant cis eQTL for POLG in nerve (P=3.90×10-13) and skin tissues (P=2.50×10-11). Consistently, mRNA level of POLG was differentially expressed in leprotic skin lesions. CONCLUSIONS: Genetic variants of TFAM and POLG were associated with leprosy in Han Chinese, presumably by affecting gene expression.
Asunto(s)
Pueblo Asiatico/genética , ADN Polimerasa gamma/genética , Proteínas de Unión al ADN/genética , Lepra Multibacilar/genética , Lepra Paucibacilar/genética , Proteínas Mitocondriales/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , China , Variaciones en el Número de Copia de ADN/genética , Replicación del ADN/genética , ADN Mitocondrial/genética , Exones/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lepra Multibacilar/patología , Lepra Paucibacilar/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ADN , Piel/patología , Adulto JovenRESUMEN
Leprosy is a chronic infectious and neurological disease caused by Mycobacterium leprae, an unculturable pathogen with massive genomic decay and dependence on host metabolism. We hypothesized that mitochondrial genes PARL and PINK1 would confer risk to leprosy. Thirteen tag SNPs of PARL and PINK1 were analyzed in 3620 individuals with or without leprosy from China. We also sequenced the entire exons of PARL, PINK1 and PARK2 in 80 patients with a family history of leprosy by using the next generation sequencing technology (NGS). We found that PARL SNP rs12631031 conferred a risk to leprosy (Padjusted = 0.019) and multibacillary leprosy (MB, Padjusted = 0.020) at the allelic level. rs12631031 and rs7653061 in PARL were associated with leprosy and MB (dominant model, Padjusted < 0.05) at the genotypic level. PINK1 SNP rs4704 was associated with leprosy at the genotypic level (Padjusted = 0.004). We confirmed that common variants in PARL and PINK1 were associated with leprosy in patients underwent NGS. Furthermore, PARL and PINK1 could physically interact with each other and were involved in the highly connected network formed by reported leprosy susceptibility genes. Together, our results showed that PARL and PINK1 genetic variants are associated with leprosy.
Asunto(s)
Lepra/genética , Metaloproteasas/genética , Proteínas Mitocondriales/genética , Proteínas Quinasas/genética , Adolescente , Adulto , Anciano , Pueblo Asiatico/genética , Niño , Preescolar , China , Exones , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Adulto JovenRESUMEN
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae), which has massive genomic decay and dependence on host metabolism. Accumulating evidence showed a crucial role of mitochondria in metabolism and innate immunity. We hypothesized that the mitochondrial-related antimicrobial/antiviral immune genes MAVS (mitochondrial antiviral signaling protein), MITA (mediator of IRF3 activation) and MFN2 (mitofusin 2) would confer a risk to leprosy. In this study, we performed a case-control study to analyze 11 tag and/or non-synonymous SNPs of the MAVS, MITA and MFN2 genes in 527 leprosy patients and 583 healthy individuals, and directly sequenced the three genes in 80 leprosy patients with a family history from Yunnan, Southwest China. We found no association between these SNPs and leprosy (including its subtypes) based on the frequencies of alleles, genotypes and haplotypes between the cases and controls. There was also no enrichment of potential pathogenic variants of the three genes in leprosy patients. Our results suggested that genetic variants of the MAVS, MITA and MFN2 genes might not affect the susceptibility to leprosy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Pueblo Asiatico/genética , GTP Fosfohidrolasas/genética , Lepra/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , China , Femenino , Estudios de Asociación Genética , Humanos , Lepra/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
OBJECTIVE: This study was conducted to evaluate the effectiveness of uniform multi-drug therapy (UMDT) in patients with multibacillary (MB) leprosy. METHODS: Newly detected MB leprosy patients were treated with six months of UMDT as recommended by the World Health Organization (WHO). The effectiveness of treatment was evaluated by clinical status and skin smear tests. RESULTS: At the start, 114 patients were recruited, examined, and treated. These patients were re-examined and followed annually for up to six years. A total of 75 (65.8%) patients completed six years of follow-up. Dropouts were attributable to death, severe drug reactions, and other reasons. The mean ± standard deviation bacteriological index (BI) of all patients decreased from 3.01 ± 1.50 before treatment to 0.02 ± 1.84 at the end of year 6, reflecting a mean annual decrease of 0.50. The rate of smear negativity in all patients was 98.7% at the end of year 6 of follow-up. A total of 53 leprosy reactions were observed. One patient relapsed 13 months after the cessation of treatment. CONCLUSIONS: A 6-month administration of UMDT is effective in MB leprosy patients. The changes in BI values and the frequency of leprosy reactions were similar to those cited in reports in the literature of patients treated with 1- or 2-year regimens of MDT. However, further research should be conducted to confirm the present results.